TLRs play a pivotal role in acquired immunity by triggering the maturation of dendritic cells (DC) to competent antigen presenting cells (APC), capable of priming naive T cells. Because TLR3 triggers a unique activation pathway, we hypothesized that antigen-bearing DC activated by dsRNA would generate an acquired response different from DC activated with other PAMPs. Based upon our previous observations that the capacity of different length dsRNA oligonucleotides to activate TLR3 depended upon levels of TLR3 expression, we asked how DCs respond to different length dsRNA oligos, and how these DC activate naive T cells, especially in comparison with the TLR9 PAMP, CpG DNA. We have shown that TLR3 is expressed mainly by the CD8+ DC in mice and that only these DC respond to dsRNA oligonucleotides ranging from 60-500 bp in length. By contrast, other CD11b+ DC also respond to pI:pC, a synthetic dsRNA analogue. However, activation in this case was TLR3 independent, Mda5-dependent. Thus pI:pC and dsRNA behave differently in their capacities to activate DC. We have found that DC respond differently to dsRNA than to CpG DNA with regard to cytokines produced, surface phenotype, and activation of naive T cells. Studies are underway to determine the intracellular compartments where dsRNA meets TLR3 in different DC subsets, and to compare the in vivo priming capacities of immunogens containing antigen and different length dsRNA oligos, or CpG DNA. An overall goal of these studies is to fine-tune PAMP adjuvants to generate immune responses specific for particular classes of pathogens. In the case of dsRNA, a viral PAMP, we would expect the response to be especially effective against viral pathogens.